Multifunctional Adenine-functionalized Supramolecular Micelles-Selective Cell Internalization and Chemotherapy against Cancer Cells

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研究生：	Fasih Bintang Ilhami Fasih Bintang Ilhami
論文名稱：	Multifunctional Adenine-functionalized Supramolecular Micelles-Selective Cell Internalization and Chemotherapy against Cancer Cells Multifunctional Adenine-functionalized Supramolecular Micelles-Selective Cell Internalization and Chemotherapy against Cancer Cells
指導教授：	高震宇 Chen-Yu Kao 鄭智嘉 Chih-Chia Cheng
口試委員:	蔡協致 Hsieh-Chih Tsai 何明樺 Ming-Hua Ho 方致元 Chih-Yuan Fang 余承佳 Cheng-Chia Yu
學位類別：	博士 Doctor
系所名稱：	應用科技學院 - 應用科技研究所 Graduate Institute of Applied Science and Technology
論文出版年：	2020
畢業學年度：	109
語文別：	英文
論文頁數：	130
中文關鍵詞：	腺嘌呤、自組裝、多功能超分子微胞、氫鍵、藥物傳輸、選擇性內化、化學光動力療法、癌細胞
外文關鍵詞：	Adenine, Self-assembly, Multifunctional supramolecular micelle, Hydrogen bond, Drug delivery, Selective internalization, Chemophotodynamic therapy, Cancer Cell
相關次數：	點閱：288 下載：4
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現今有許多治療癌症的方法，化學療法是最常被選用的的療程。傳統的化療方法有許多缺點，例如: 藥物溶解性不佳，無法專一性針對癌細胞。這些缺點造成正常細胞的傷害，也嚴重影響治療的效用與效率。藥物傳輸系統可將欲傳遞物質專一性的帶入體內特定部位。在癌症藥物的傳輸方面，奈米科技的運用，使藥物以特殊的尺寸傳遞，且可因應需求做功能上的調整，因此受到相當多的討論。其中，反饋刺激的高分子材料 (Stimuli-responsive polymeric materials, SRPMs)，可在受到特定刺激時改變其結構，這樣隨外界刺激改變物理性質的特性，獲得廣泛的關注。超分子型高分子微胞(Supramolecular polymeric micelles) 因具有良好的氫鍵結構，可自組裝成具有特殊物理性質的材料，特殊性質如:可調整的親和性，高專一性，具可逆性。以氫鍵媒介組合而成的高分子，已被用於模仿細胞核內核醣核酸與去氧核醣核酸鹼基對的微結構，作為藥物傳遞系統的架構。
在本研究中，具雙腺嘌呤端基的超分子型高分子，在經過多重氫鍵的交互作用後，可在水中或液態緩衝液中形成球狀微胞。具腺嘌呤官能基的超分子型高分子微胞 (Adenine-functionalized supramolecular polymers micelles, A-PPG micelles) 具有許多特殊的性質，例如:雙極性，可調整且可逆的感溫性相變態，球形結構，微胞大小可調控。在藥物傳輸上，酸鹼值與溫度改變可調控藥物的性質與釋放。體外細胞毒性與流式細胞分析的結果顯示，載藥微胞可有效地在不傷害正常細胞的狀況下，降低癌細胞的存活率。
再者，A-PPG微胞，可增加藥物在水溶液中遞送至腫瘤的效率。因此此種微胞，在建構有效的癌症化療方法上，值得期待。由於微胞結構中含有核鹼基氫鍵，包埋的藥物長期在富含血清的培養基中仍保持穩定；而在微酸性環境下，能快速釋放藥物。更重要的是，在體外細胞毒性與流式細胞分析中，可清楚的觀察到載藥的A-PPG微胞，對於癌細胞有高度專一性，且可快速地被癌細胞胞吞，誘發癌細胞凋亡；然而，正常細胞並不會胞吞A-PPG微胞，且不會影響其生長。上述結果在分別包埋兩種不同的抗癌藥物 (厚朴酚, Magnolol和阿黴素Doxorubicin) 的實驗中均可觀察到。驗證具腺嘌呤結構的A-PPG微胞可顯著提高癌細胞專一性胞吞作用與凋亡。此種特性可以增進化療的效用與安全性。
在接續的研究中，為了讓使藥物釋放更精準，我們將5-氨基酮戊酸 (photosensitizer 5-aminolevulinic acid, 5-ALA) 結合進A-PPG微胞，使微胞具光化學治療(photo-chemotherapy) 的功能。在雷射照射下，5-胺基乙酰丙酸 (5-aminolevulinic acid,5-ALA) 可轉換為原紫質IX (protoporphyrin IX, PpIX)，原紫質IX會誘導微胞產生的活性含氧物(oxygen species)，進而使阿黴素的大量釋放。在體外實驗中，同時包埋阿黴素和5-氨基酮戊酸A-PPG的微胞，在雷射照射下，與未照射對照組相比，對於癌細胞有較高的細胞毒性。因此A-PPG微胞作為奈米級媒介，在提升癌症化療的安全性和效益上，有極大的潛力。

Among the various cancer treatments that are currently available, chemotherapy is often not the best treatment option, but remains the most common choice for the majority of cancer patients. Traditional chemotherapy possesses have a range of disadvantages, including poor drug solubility, lack of target specificity and serious side-effects into physiological normal conditions that lead to extremely ineffective and efficient for cancer treatment. A drug delivery system is defined as the ability to bring an agent from outside the body to a specific targeted site in the body. As a means of delivering the chemo-drug, nanotechnology has received enormous attention due to their unique size, dynamics and addible functional moiety according to the needs. Stimuli-responsive polymeric materials (SRPMs) have received a great deal of interest as their structures and physical properties can be altered in response to a stimulus, and revert to their original structures when another stimulus is applied. Supramolecular polymeric micelles with well-defined hydrogen-bonding motifs allow the supramolecular polymer chains to rapidly self-assemble into materials with unique physical properties, such as controlled affinity, high specificity, and reversibility. Hydrogen-bonding mediated polymer assemblies have been designed to mimic the nucleobase paired nanostructures formed within Ribonucleic acid (RNA) and Deoxyribonucleic acid (DNA) could building blocks for a unique stimuli-responsive polymeric material as drug delivery system
In the present study, supramolecular polymer containing difunctional adenine-containing end groups to form nano-spherical micelles in water and aqueous buffer solutions through multiple hydrogen-bonding interactions. Adenine-functionalized supramolecular polymers (A-PPG) micelles exhibits a number of interesting properties, including unique amphiphilic behavior, tunable and reversible thermo-responsive phase transitions, desirable spherical morphology and controllable size, as well as tunable drug-loading properties and well-controlled drug release capability by pH and thermos-responsive. In vitro cytotoxicity assays and flow cytometry demonstrated that drug-loaded micelles could potentially be employed to selectively and effectively deliver drugs to cancer cells and rapidly reduce tumor cell viability, without harming normal cells. Second, adenine-functionalized supramolecular polymers (A-PPG) in aqueous solution enhance the efficiency of drug delivery to solid tumors in order to further advance supramolecular polymer micelles as a promising platform for efficient cancer chemotherapy. Due to the presence of nucleobase hydrogen bonding within the structure of the micelles, drug-loaded A-PPG micelles exhibit long-term drug-entrapment stability in serum-rich media and rapid drug release under mildly acidic conditions. Importantly, cytotoxicity assays and flow cytometric analysis clearly demonstrated that the drug-loaded A-PPG micelles were highly selectively and rapidly endocytosed by cancer cells and effectively triggered apoptotic tumor cell death, but were not internalized and did not affect the cell viability of normal cells. The same effects were observed using two different anticancer drugs, indicating that the adenine moieties within A-PPG significantly increased the tumor-selective cellular uptake and cytotoxicity of supramolecular micelles, substantially enhanced the response to chemotherapy and could improve the safety and effectiveness of the cancer treatment.
For the next studies, to enable high levels of well-controlled drug release in cancer cells, incorporation of photosensitizer 5-aminolevulinic acid (5-ALA) within adenine-functionalized supramolecular micelles (A-PPG) to achieve effective drug delivery combined with photo-chemotherapy. Under laser irradiation, the generate of reactive oxygen species generation of DOX/5-ALA-loaded A-PPG micelles due to triggered by PpIX converted from ALA in micelles, thereby promoting the burst release of DOX from micellar. In vitro assay demonstrated that treatment with double cargo of DOX/5-ALA-loaded A-PPG micelle under laser irradiation is higher cytotoxicity than non-irradiated in cancer cell and effectively induced apoptotic cell death via endocytosis. Thus, developed Adenine-functionalized supramolecular polymers (A-PPG) micelles has great potential as nanovector to improve the safety and efficacy of cancer chemotherapy.

CHINESE ABSTRACT ........................................................................................ i
ABSTRACT ................................................................................................... iii
ACKNOWLEDGMENTS ............................................................................. v
TABLE OF CONTENS ................................................................................. vi
ABBREVIATIONS ........................................................................................ viii
LIST OF FIGURES ....................................................................................... x
LIST OF TABLES ......................................................................................... xv
LIST OF SCHEMES ..................................................................................... xvi
CHAPTER-1 .................................................................................................. 1
1. Introduction ................................................................................................. 1
1.1 Background ................................................................................................ 1
1.2 Objectives of the Thesis ............................................................................. 3
1.3 Materials, Reagents and Instruments .......................................................... 4
1.3.1 Materials and Reagents ...................................................................... 4
1.3.2 Instruments ........................................................................................ 5
1.3.3 Statistical Analysis ............................................................................ 5
CHAPTER-2 .................................................................................................. 7
2. Literature Review ........................................................................................ 7
2.1 Overview of Cancer ................................................................................... 6
2.2 Therapeutic of Cancer Modalities ............................................................... 12
A. Surgery .................................................................................................. 12
B. Radiation Therapy ......................................................................................... 12
C. Chemotherapy ....................................................................................... 13
D. Hyperthermia Therapy ........................................................................... 14
E. Immunotherapy ...................................................................................... 14
F. Role of Stem Cells in Cancer Treatment ................................................. 16
G. Photodynamic Therapy .......................................................................... 16
2.3 Nanomedicine in Cancer Therapy .............................................................. 17
2.3.1 Principle of Nanomedicine ...................................................................... 17
2.3.2 Advanced Functionalities Nanomedicine in Cancer Therapy ................... 19
2.4 Nanocarrier for Cancer Therapy ................................................................. 21
2.4.1 Liposomes ............................................................................................... 21
2.4.2 Dendrimers ............................................................................................. 22
2.4.3 Polymers ................................................................................................. 22
2.4.4 Micelles .................................................................................................. 23
2.4.5 Stimuli-responsive Polymeric Micelles.................................................... 24
2.5 Functional Systems Derived from Nucleobase Self-Assembly
for Drug Delivery ....................................................................................... 27
2.6 Adenine-functionalized Supramolecular Micelles ....................................... 29
CHAPTER-3 .................................................................................................. 31
3. Experimental Methods ................................................................................. 31
3.1 Synthesis of Adenine-functionalized polypropylene glycol (A-PPG) .......... 31
3.2 Synthesis of Uracil-functionalized polypropylene glycol (U-PPG) ............. 31
3.3 Critical micelle concentration (CMC) ......................................................... 31
3.4 Dynamic Light Scattering (DLS) and Zeta Potentials ................................. 32
3.5 Transmittance measurements and determination of LCST .......................... 32
3.6 Atomic Force Microscopy (AFM) .............................................................. 32
3.7 Preparation of Magnolol/DOX-loaded supramolecular micelles ................. 32
3.7.1 Encapsulation of Magnolol-loaded Supramolecular Micelles ................... 32
3.7.2 Encapsulation of DOX-loaded Supramolecular Micelles ......................... 33
3.7.3 Encapsulation of 5-ALA-loaded Supramolecular Micelles....................... 33
3.8 In vitro Drugs Release Assay ..................................................................... 34
3.9 Long-term Kinetic Stability ........................................................................ 34
3.10 Cell culture .............................................................................................. 35
3.11 In vitro cytotoxicity studies ...................................................................... 35
3.12 Analysis of cellular uptake by confocal laser scanning microscopy .......... 36
3.13 Intracellular ROS assay ............................................................................ 36
3.14 Detection of Fluorescence Intensity by Flow Cytometry ........................... 37
3.15 Flow Cytometric Analysis of Apoptosis by Annexin V/PI
Double Staining ......................................................................................... 37
CHAPTER-4 .................................................................................................. 38
4. Multifunctional Adenine-Functionalized Supramolecular Micelles for Highly
Selective and Effective Cancer Chemotherapy ............................................. 38
4.1 Introduction ............................................................................................... 38
4.2 Result and Discussion ................................................................................ 41
4.3 Conclusion ................................................................................................. 49
CHAPTER-5 .................................................................................................. 51
5. Adenine-Functionalized Supramolecular Micelles for Selective Cancer Chemotherapy ............................................................................................. 51
5.1 Introduction ............................................................................................... 51
5.2 Result and Discussion ................................................................................ 54
5.3 Conclusion ................................................................................................. 63
CHAPTER-6 .................................................................................................. 65
6. Multifunctional Light-Triggered Supramolecular Micelles with Enhanced Controlled Drug Release and Improved Chemotherapeutic Efficacy ............ 65
6.1 Introduction ............................................................................................... 65
6.2 Result and Discussion ................................................................................ 69
6.3 Conclusions ............................................................................................... 78
CHAPTER-7 .................................................................................................. 79
7. Summary and Outlook ................................................................................. 79
7.1 Summary.................................................................................................... 79
7.2 Outlook ...................................................................................................... 79
REFERENCE................................................................................................. 81
APPENDIX .................................................................................................... 99
Supportive Information ................................................................................. 99
Publications .................................................................................................... 110

                                

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